An extraordinary number of cellular processes are regulated by the tyrosine phosphorylation of a diversity of proteins. Tyrosine phosphorylation is induced by a plethora of receptor-like molecules as well as by a wide range of intracellular enzymes. The effects of tyrosine phosphorylation are numerous, and they modulate a range of developmental as well as other cellular operations. Of course, the importance of tyrosine phosphorylation is underlined by the need for mechanisms which carefully regulate the levels of these events. Thus, protein tyrosine kinases represent positive mediators of tyrosine phosphorylation, while protein tyrosine phosphatases (PTPs) induce the removal of phosphate from tyrbsine. The balance of the levels of tyrosine phosphate is thus mediated by the relative activities of these two types of enzymes. It is therefore clear that the mechanisms which regulate cellular function via tyrosine phosphorylation require specific proteins which mediate both the upregulation as well as the downregulation of the levels of this modified amino acid.
PTPs represent a growing family of enzymes that are found in both receptor as well as non-receptor forms (Tonks, Semin. Cell. Biol. 4:373-453 (1993), Walton et al., Ann. Rev. Biochem. 62:101-120 (1993) and Sun et al., Trends Biochem. Sci. 19(11):480-485 (1994)). Non-receptor PTPs are a highly diverse kindred, and they contain a number of motifs, in addition to the enzymatically active PTP domain, that serve to regulate the region of the cell occupied by these proteins as well as the substrate specificity of these enzymes. The receptor PTPs are also a highly diverse group that are unified by the inclusion of a transmembrane domain which disposes them to the plasma membrane of the cell. Recently, the receptor PTPs have been subdivided into 8 types based upon their domain content (Brady-Kalnay et al., Curr. Opin. Cell. Biol. 7(5):650-657 (1995)). These subtypes all contain one or two PTPase domains on their cytoplasmic sides, with a variety of extracellular motifs including heavily O-glycosylated mucin-like domains (for example, CD45), chondroitin sulfate domains (for example, PTP .gamma.) and short, highly glycosylated segments (for example, PTP .alpha.). The largest family of PTPs is the family which contains various motifs related to those found in adhesion molecules. These motifs include immunoglobulin-like (IgG) domains and fibronectin type III (FnIII) regions similar to those found in cell adhesion molecules such as ICAM, N-CAM and Ng-CAM (Rao et al., J. Cell. Biol. 118:937-949 (1992)). In addition, a subset of these adhesion-like PTPs, including the PTPs .kappa. and .mu., contain a third domain termed the MAM, for meprin/A5/PTP .mu., motif (Beckman et al., Trends Biochem. Sci. 18:40-41 (1993)). The MAM motif has been previously shown to be involved with cell-cell recognition in neurons (Jiang et al., J. Biol. Chem. 267:9185-9193 (1992), Takagi et al., Neuron 7:295-307 (1991) and Hirata et al., Neurosci. Res. 17:159-169 (1993)). Interestingly, recent data suggest that three of these adhesion-like PTPs appear to be involved with neuronal pathfinding during Drosophila development (Desai et al., Cell 84:599-609 (1996) and Kreuger et al., Cell 84:611-622 (1996)). Together, these structural data are consistent with the conjecture that receptor PTPs encompass a diverse family of enzymatically active proteins which contain a number of interesting cell surface motifs potentially involved with the sensing of the extracellular environment.
PTPs .kappa. and .mu. are the receptors that are most well characterized as adhesion molecules (Brady-Kalnay et al., supra, Jiang et al., Mol. Cell. Biol., 13:2942-2951 (1993) and Gebbink et al., Febs. Lett. 290(1-2):123-130 (1991)). Both of these PTPs have been demonstrated to mediate homotypic adhesion. Thus, a diversity of assays, including cell- as well as molecule-based, have demonstrated that the extracellular domain of these enzymes can bind with high specificity in a homophilic manner (Brady-Kalnay et al., J. Cell. Biol. 268:961-972 (1993), Gebbink et al., J. Biol. Chem. 268:16101-16104 (1993) and Sap et al., Mol. Cell. Biol. 14:1-9 (1994)). Interestingly, mixing experiments have revealed that these closely related PTPs will not bind to each other in a heterophilic mode, suggesting that the extracellular domain is meant to recognize other cells specifically expressing identical receptors, a situation highly reminiscent of the cadherin homotypic adhesion system (Kemler et al., Trends Genet. 9:317-321 (1993)). While the extracellular domains required for this homotypic binding remain controversial, it appears likely that both the MAM motif as well as the IgG region are involved with homophilic interactions (Brady-Kalnay et al., J. Biol. Chem. 269:28472-28477 (1994) and Zondag et al., J. Biol. Chem. 270(24):14247-14250 (1995)). While these data suggest that these homophilic adhesion enzymes are involved with the recognition of other cells expressing similar types of receptors, other data have suggested that this recognition event may play a role in the attachment of such cells to each other. Thus, Tonks and colleagues have recently demonstrated that the receptor PTP .mu. specifically associates with the catenin/cadherin complex of homotypic cell adhesion molecules (Brady-Kalnay et al., J. Cell. Biol. 130(4):977-986 (1995)). They also demonstrated that treatment of cells with the PTP inhibitor pervanadate resulted in the upregulation of tyrosine phosphorylation of cadherins and catenins, a result which suggested a role for a PTP, potentially PTP .mu., in the maintenance of the cadherin/catenin complex in an underphosphorylated state. Interestingly, previous work suggested that the level of tyrosine phosphorylation of this complex was correlated with the adhesive capacity of the cadherins (Beherns et al., J. Cell. Biol. 120:757-766 (1993)), a result which is consistent with the hypothesis that the adhesion between cells mediated by the cadherins might be regulated by their tyrosine phosphorylation levels as determined by homotypic interactions between receptor PTP s such as .kappa. and .mu..
The finding that PTPs .kappa. and .mu. mediated homotypic adhesion, together with the somewhat restricted tissue distribution of these PTPs (Jiang et al., (1993) supra and Gebbink et al., (1991) supra), has suggested that additional members of this family of adhesive enzymes might exist. Here we report the cloning and characterization of the third member of this receptor PTP family, termed PTP .lambda.. The PTP .lambda. polypeptide reported here contains structural motifs that are very similar to those found in PTP .kappa. and .mu.. In addition, this novel PTP .lambda. receptor reveals a tissue distribution that is divergent from that previously described for the other members of this family.